A case of a new Lynch Syndrome variant with a deletion, c.1024_1026, in the MSH2 gene in a Chinese family

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Abstract
Background Multiple genetic variations have been identi ed in mismatch repair genes for Lynch Syndrome. However, diagnosis of Lynch Syndrome and its subtypes in patients with atypical cancer types still remains challenging. Little is known about Lynch syndrome-related renal carcinoma and related genes. We present a case of renal carcinoma with multiple primary skin tumors, with a new Lynch Syndrome variant with a deletion in a Chinese family.
Case presentation: The patient was a 60-year-old Chinese male with a history of Lynch Syndrome-related renal carcinoma with repeatedly multiple primary skin tumors. Immunohistochemistry revealed loss of MSH2 and MSH6 proteins. Sequencing of mismatch repair genes revealed a previously unknown germline MSH2 mutation (c.1024_1026 del) resulting in an amino acid deletion (p. V342del). This variant was co-segregated among the carcinoma-affected family members. After 6 cycles of immunotherapy, a marked regression of the skin tumor was obtained.

Conclusions
We clarify the pathogenic signi cance of this new mutation and suggest immunotherapy for patients with this subtype of Lynch Syndrome.

Background
Lynch Syndrome (LS) is an autosomal dominant disorder, previously known as hereditary nonpolyposis colorectal cancer, that carries a high risk of colorectal and other cancers [1,2]. The pathogenesis is associated with DNA mismatch repair (MMR) gene mutations including those in MLH1, MSH2, MSH6, PMS2, and EPCAM [3,4]. These mutations cause de ciencies in DNA repair, resulting in a high frequency of replication errors. Genetic analysis and detection of protein expression by immunohistochemistry (IHC) are important in diagnosing LS [5,6]. MTS is primarily related to mutations in MSH2 and is characterized by skin tumors (such as sebaceous adenomas, skin squamous cell carcinomas) [9]. However, MTS-related primary renal carcinoma with skin tumors is rarely reported. We report a case of LS originating in renal cell carcinoma with multiple primary tumors and a previously unknown MSH2 mutation (c.1024_1026 del).

Case Presentation
The proband has a history of various cancers. In 2001, at the age of 41 years, he was diagnosed with left kidney clear cell carcinoma; in 2008, with right lung clear cell carcinoma due to renal tumor metastasis; and in 2010, with bone metastases. In 2019, he had a rectal submucosal neuroendocrine tumor. He received the standard treatment each time.
In addition to the internal carcinomas, the proband also presented sequentially with multiple neoplasms located on the skin of the head and neck or upper chest, with faster growth starting in 2013 (Fig. 1). The pathology on excised skin lesions revealed primary benign and malignant tumors, including skin squamous cell carcinoma, keratoacanthoma, sebaceous adenoma, and sebaceous gland carcinoma Further analysis showed that the mutation had been inherited for three consecutive generations in the family (Fig. 3).

Clinical diagnosis
Consideration of the multi-primary cancers, the family history, and the genetic testing results led to the diagnosis of LS subtype MTS, based on the Amsterdam II criteria. The MSH2 mutation (c.1024_1026del) will be documented in the genetic database.

Clinical treatment
Based on the result of MMR gene defects and MSI-high, the proband was treated with sintilimab, an inhibitory antibody that binds to PD-1, at 200 mg per 3-week cycle. After 6 cycles, there were no new skin tumors for nearly 5 months, and the size of the largest skin tumor decreased from 0.9 × 0.6 to 0.2 × 0.1 cm (Fig. 1). The patient's condition is stable, and the e cacy of immunotherapy is being monitored.

Discussion And Conclusions
The presence of multiple sebaceous glands is a sign of MMR gene defects and may be a useful clinical parameter for diagnosing the MTS subtype of LS [10]. Approximately 70-75% of LS cases are caused by mutations in MSH2 and MLH1 [11]. The in-frame deletion of MSH2 identi ed in this study (c.1024_1026 del) has not been reported previously. We have proposed the correlation of the gene with LS/MTS, which clari es the prognosis of the proband, and provides guidance for early cancer screening for the family descendants. Future development of in silico analysis may facilitate opportune screening, diagnosis, and prevention.
Irradiation and excision of skin tumors and the use of isotretinoin to prevent recurrence with monitoring for early detection of visceral tumors may be bene cial as treatments for LS/MTS [12,13].
Immunotherapy in LS is mostly used for the treatment of multiple visceral metastases [14], and there is lack of evidence for the treatment of repeated skin tumors. Our results suggest that LS/MTS patients with di cult-to-control skin tumors can bene t from immunotherapy, and the treatment possibly has a preventive effect on the progress of subsequent visceral cancers, which raises a challenge to monitor the effectiveness of immunotherapy. Further studies are needed to provide more conclusive evidence.
In conclusion, the in-frame deletion of MSH2 (c.1024_1026 del) is supposed to be the pathogenic new mutation for LS/MTS, and immunotherapy is a treatment strategy that can be considered for patients with this subtype of Lynch Syndrome.

Consent for publication
The proband and his family have approved publication of this report.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.